Clinical trial challenges long held beliefs about treating brittle bone disease

Increasing bone density in patients with a rare genetic condition that causes bones to break easily does not prevent fractures, a large clinical trial has found.

Patients with brittle bone disease who were given treatments to boost their bone density experienced a similar number of fractures as those who received standard care.

The findings challenge the long-held belief that better bone density could help those with the condition and suggest treatment strategies should instead focus on improving bone quality, experts say.

Brittle bone disease, or osteogenesis imperfecta (OI), is caused by a defect in collagen production – a protein essential for bone structure – leading to weak, fragile bones that can break with little or no trauma. It affects around 1 in every 15,000 people.

For decades, treatment of the condition has focused on giving drugs that increase bone density, even though there is little evidence that this reduces fracture risk.

Scientists at the University of Edinburgh followed 350 adults with OI over eight years, from May 2017 to March 2025, in the TOPaZ trial. Half of the patients received drug treatments designed to improve bone density, while the remaining half received standard care.

While those on the drug treatment had significantly increased bone density compared to those receiving standard care, this did not lead to a reduction in the total number of new fractures or fractures in the spine. 37 percent of those who received bone density treatment experienced fractures, compared with 36 percent of those who received standard care.

The findings could help to reshape treatment approaches for OI, moving towards therapies that strengthen bone quality to limit disease progression and improve outcomes for patients, experts say.

The study, supported by the Brittle Bone Society and funded by the Medical Research Council and National Institute for Health and Care Research, is published in the journal JAMA. The research team included scientists from 27 hospitals across the UK and Europe, providing specialist care for patients with OI.

The results of this study will fundamentally change clinical practice with regard to the treatment of osteogenesis imperfecta. We have been using drugs to increase bone density for decades in the hope that they might prevent fractures but the TOPaZ trial clearly shows that these medicines simply do not work. We now need to focus efforts on finding new drugs that can target the defects in bone collagen to improve the strength of bone and reduce fracture risk in this rare but serious disease."

Stuart Ralston, Study Lead and Professor, Institute of Genetics and Cancer, University of Edinburgh 

Patricia Osborne, CEO of Brittle Bone Society, said: "We are proud to have supported the TOPaZ trial. The results have given patients and clinicians clear evidence to guide treatment decisions and highlight the importance of OI-specific research. This study also shows the vital role that charity-supported research plays in challenging assumptions and ensuring people with OI receive care based on robust evidence. By bringing together the largest group of adults with OI studied to date, TOPaZ sets a new benchmark and will directly influence how future trials are designed and delivered."